Insights from transgenic mice regarding the role ofbcl-2 in normal and neoplastic lymphoid cells

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Abstract
Thebcl-2 gene was first discovered by molecular analysis of the 14; 18 chromosome translocation which is the hallmark of most cases of human follicular lymphoma. To date, it is unique among proto-oncogenes because, rather than promoting cell proliferation, it fosters cell survival. This review summarizes the impact of constitutivebcl-2 expression on the development and function of lymphocytes as well as their malignant transformation. Expression of abcl-2 transgene in the B lymphoid compartment profoundly perturbed homeostasis and, depending on the genetic background, predisposed to a severe autoimmune disease resembling human systemic lupus erythematosus. T lymphoid cells from transgenic mice were remarkably resistant to diverse cytotoxic agents. Nevertheless, T lymphoid homeostasis was unaffected and tolerance to self was maintained. Expression of high levels of Bcl-2 facilitated the development of B lymphoid tumours but at relatively low frequency and with long latency. Co-expression ofmycandbcl-2, on the other hand, promoted the rapid onset of novel tumours which appeared to derive from a lympho-myeloid stem or progenitor cell. Introduction of thebcl-2 transgene into scid mice facilitated the survival and differentiation of pro-B but not pro-T cells, suggesting that a function necessary to supplement or complement the action of Bcl-2 is expressed later in the T than the B lineage. Crosses of thebcl-2 transgenic mice with p53- /- mice have addressed whether loss of p53 function and gain ofbcl-2 function are synergistic for lymphoid cell survival.